tbuckley/cabot-search huggingface dataset:
Abstract 4598: Vitamin b1 derivative, benfotamine, prevents VEGF-induced angiogenesis
Authors: Kieran V. Allowitz, Trevor J. Plowman, Kota V. Ramana
Journal: Cancer Research (2023)

Abstract Several studies have indicated that thiamine, and more specifically its lipid soluble derivative benfotiamine, exerts an anti-oxidative and anti-inflammatory effect on the body. However, its effect in preventing cancer cell proliferation, migration, invasion, and metastasis is not yet clearly understood. It is known that angiogenesis plays a significant role in the growth and spread of many cancers but the role of benfotiamine in neovascularization is not yet known. Therefore, in this study, we hypothesized that benfotiamine would prevent VEGF-induced angiogenesis in vitro and in vivo. To examine this, we have treated human umbilical vein endothelial cells (HUVECs) with VEGF (Vascular Endothelial Growth Factor; 10 ng/ml) in the absence and presence of benfotiamine (0-100 uM) in a time and dose-dependent manner. We then examined the cell viability by MTT assay and apoptosis by Annexin-V staining and found that benfotiamine alone had minimal effect on cell viability and it prevents VEGF-induced cell proliferation. In vitro angiogenesis assay indicates that benfotiamine prevented the VEGF -induced tube formation of HUVECs. Further, benfotiamine regulated the expression of VEGF-induced growth factors such as VEGF, PIGF, IGFBP-1, ECGF, FGF-1 and 2, anti-angiogenic enzymes such as Serpin E1, TIMP-1, MMP-8, TSP-1, PTX3 and uPA and cytokines such as IL-8, Prolactin, ET-1, Endostatin, and CCL3. We will next examine how benfotiamine prevents in vivo angiogenesis by utilizing a rat Matrigel plug model of angiogenesis in rats. The Matrigel sections will be stained with CD36, vWF, and other angiogenic markers to visualize the effect of benfotiamine on VEGF-induced angiogenesis. In conclusion, our current results indicate that benfotiamine has anti-angiogenic potential via inhibition of various pro-angiogenic growth factors and promoting anti-angiogenic factors in vitro and in vivo. Thus, our studies demonstrate that benfotiamine could be further developed as a novel therapeutic agent to prevent cancer growth and metastasis. Citation Format: Kieran V. Allowitz, Trevor J. Plowman, Kota V. Ramana. Vitamin b1 derivative, benfotamine, prevents VEGF-induced angiogenesis. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4598.
Abstract 5985: Cyclin dependent kinase 9 (CDK9) inhibition increased efficacy of programmed cell death protein 1 (PD-1) blockade for hepatocellular carcinoma (HCC) through decreasing programmed death-ligand 1 (PD-L1) expression
Authors: Ching-Tso Chen, Yu-Yun Shao, Hung-Wei Hsu, Rita R. Wo, Han-Yu Wang, Ann-Lii Cheng, Chih-Hung Hsu
Journal: Cancer Research (2023)

Abstract Background: PD-1 blockade has been approved as treatment for advanced HCC. We previously demonstrated the efficacy of CDK9 inhibition in reducing the expression of inducible proteins and as a treatment for HCC (Shao et al. Oncology 2022). We thus examined the influence of CDK9 inhibition on the expression of PD-L1 in HCC and the potential of improving the efficacy of PD-1 blockade with the combination of CDK9 inhibitors. Methods: We first examined the influence of specific CDK9 inhibitors, AZD4573 and atuveciclib, on interferon-γ (IFN-γ) induced PD-L1 expression of human HCC cell lines HuH7 and Hep3B. Overexpression of CDK9 and siRNA to CDK9 were used to confirm the findings. Similar experiments were repeated in the mouse HCC cell line BNL. To test the in vivo efficacy, we orthotopically implanted BNL cells in the subcapsular area of BALB/c mice, which were then treated with vehicle, CDK9 inhibitors, anti-PD-L1 antibodies, or their combination. To compare with tumor sizes, all mice were sacrificed after 14 days of treatment. To compare survival, the mice were only sacrificed if they met the criteria of animal euthanasia. Results: Both HuH7 and Hep3B cells had minimal PD-L1 expression, which however could be induced using IFN-γ. AZD4573 and atuveciclib decreased the IFN-γ induced PD-L1 expression of HuH7 and Hep3B cells in a dose dependent manner. The flow cytometry results confirmed that membrane PD-L1 expression was also decreased by CDK9 inhibition. Overexpression of CDK9 decreased the influence of these CDK9 inhibitors on PD-L1 expression. CDK9 knockdown using siRNA reduced the IFN-γ induced PD-L1 expression. AZD4573 and atuveciclib also reduce the PD-L1 expression in BNL cell lines. In the orthotopic animal model, the tumors of the sacrificed mice were significantly smaller in mice treated with atuveciclib and an anti-PD-L1 antibody than mice treatment with either alone. The survival of mice treated with the combination was also longer than mice treated with each therapy alone. Conclusion: We demonstrated that CDK9 inhibition could reduce the IFN-γ induced PD-L1 expression of HCC cells. Combination of CDK9 inhibitors and anti-PD-L1 antibodies was more effective than either therapy alone. Citation Format: Ching-Tso Chen, Yu-Yun Shao, Hung-Wei Hsu, Rita R. Wo, Han-Yu Wang, Ann-Lii Cheng, Chih-Hung Hsu. Cyclin dependent kinase 9 (CDK9) inhibition increased efficacy of programmed cell death protein 1 (PD-1) blockade for hepatocellular carcinoma (HCC) through decreasing programmed death-ligand 1 (PD-L1) expression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5985.
Abstract 1094: 3-Bromopyruvate reduces pancreatic tumor growth by damaging mitochondria and inhibiting glucose metabolism in both cell culture and mouse model
Authors: Sanjit Roy, Tijana Dukic, Binny Bhandary, Jason Molitoris, Young H Ko, Hem D Shukla
Journal: Cancer Research (2023)

Abstract Pancreatic cancer (PC) is the deadly cancer in both men and women, with a one-year relative survival rate of 20%, and a five-year relative survival rate of only 8%. Pancreatic cancer is characterized by dense fibrotic stroma that constitutes up to 90% of the total tumor volume and contains extracellular matrix (ECM), immune cells, vasculature, and cancer-associated fibroblasts which are hallmark of immunosuppressive tumor microenvironment. In present investigation we have tested anti-cancer effect of 3-BromoPyruvate (3-BP), an inhibitor of aerobic glycolysis employing Panc-2 cancer cells, and syngeneic pancreatic cancer mouse model. Panc-2 cancer cells treated with 40 uM of 3-BP showed significant inhibition in cell proliferation and ATP production. Cells treated with 60 uM dose level, showed drastic phenotypic changes (membrane blebbing) within 2 hours of treatment. The qRT PCR data showed 3BP inhibited hexokinase II (HK2) expression at 40uM, suggesting 3-BP regulate HK2 expression at transcriptional level. We also observed that 3-BP in combination with low doses of irradiation was more effective in killing cancer cells than 3-BP alone in both 2D and 3D culture model. Treatment of C57BL/6 subcutaneous pancreatic tumor model with 10 and 20 mg/kg of 3BP also showed significant reduction of tumor growth. The Transmission Electron Microscopy of tumor tissues treated with 3-BP revealed severely damaged mitochondrial structure which might have severely affected ATP generation in cancer cell. Altogether, the results in this study demonstrated that 3-BP could be a promising anti-tumor drug against pancreatic cancer and its efficacy could be improved in combination with radiation therapy. Citation Format: Sanjit Roy, Tijana Dukic, Binny Bhandary, Jason Molitoris, Young H Ko, Hem D Shukla. 3-Bromopyruvate reduces pancreatic tumor growth by damaging mitochondria and inhibiting glucose metabolism in both cell culture and mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1094.
Abstract 3352: Development and validation of a serum microRNA-based diagnostic model for early detection of multiple cancers
Authors: Grace Zhou, Hai Hu
Journal: Cancer Research (2023)

Abstract Introduction: Detecting cancer early improves patients’ survival rate. We previously developed a serum 4-microRNA (miRNA) diagnostic model using lung cancer patient samples, which detected 12 cancer types with high accuracy (Zhang and Hu 2022 Cancers). In this study, we aimed to develop a new diagnostic model based on samples from ovarian cancer patients to evaluate whether model performance depends on the initial cancer type used. Patients and Methods: Our previous work assembled a serum miRNA microarray dataset from 4 individual datasets from GEO, including 3604 patients across 13 cancer types and 3932 non-cancer controls. In this study, we composed a training set of 191 ovarian cancer patients and 191 non-cancer controls matched by age and gender. Limma analysis was performed to rank differentially expressed miRNAs, and 10-fold cross-validation was used to determine the optimal number of top miRNAs for the final diagnostic model. Model performance was evaluated by area under the curve (AUC) of Receiver Operating Characteristic (ROC) curve analysis, and sensitivity and specificity, using samples not utilized in current or previous model development. Results: Using this training set, a 10-miRNA model was developed which showed an improved AUC 0.994 as compared to 0.973 from our previous model for ovarian cancer in the testing set. AUC was also substantially improved on sarcoma and breast cancers. With 99.1% specificity, the current model demonstrated at least 70% sensitivity for 10 of the 13 cancer types, comparable to the previous model with 99.3% specificity (Table 1). Conclusion: Our study showed that blood miRNA-based diagnostic models can be developed for detecting multiple cancers with high accuracy, regardless of initial cancer types used in model development. These results suggested that tumors of different cancers shed common types of miRNAs into the bloodstream, supporting the use of circulating miRNAs as a biomarker for multi-cancer early detection. ABLE 1. Diagnostic Model Performance Cancer Type N Current Model AUC Current Model Sensitivity Previous Model AUC Previous Model Sensitivity Ovarian 142 0.994 0.80 0.973 0.69 Lung 1358 0.998 0.93 0.999 0.99 Pancreatic 149 0.992 0.76 0.983 0.83 Prostate 40 0.998 0.95 0.996 0.92 Sarcoma 132 0.973 0.52 0.876 0.72 Esophageal 124 0.995 0.90 0.990 0.85 Gastric 150 0.998 0.93 0.999 1.00 Glioma 40 0.985 0.68 0.996 0.88 Liver 348 0.988 0.70 0.979 0.84 Biliary Tract 40 0.996 0.85 0.998 0.98 Bladder 392 0.996 0.95 0.998 0.98 Breast 135 0.946 0.10 0.378 0.00 Colorectal 155 0.99 0.83 0.955 0.86 Citation Format: Grace Zhou, Hai Hu. Development and validation of a serum microRNA-based diagnostic model for early detection of multiple cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3352.
Abstract 2433: SERPINA12 promotes the tumorigenic capacity of hepatocellular carcinoma stem cells through hyperactivation of AKT/β-catenin signaling
Authors: Huajian Yu, Lei Zhou, Jane Ho-Chun Loong, Ka-Hei Lam, Tin-Lok Wong, Kai-Yu Ng, Man Tong, Victor WS Ma, Yanyan Wang, Xiang Zhang, Terence K Lee, Jing-Ping Yun, Jun Yu, Stephanie Ma
Journal: Cancer Research (2023)

Abstract Hepatocellular carcinoma (HCC) is an aggressive disease with a poor clinical outcome. Understanding the mechanisms that drive cancer stemness, which we now know is the root cause of therapy failure and tumor recurrence, is fundamental for designing improved therapeutic strategies. The aim of this study is to identify molecular players specific to CD133+ HCC to better design drugs that can precisely interfere with cancer stem cells (CSCs) but not normal stem cell function. Transcriptome profiling of epithelial-specific ‘normal’ CD133+ cells isolated from fetal and regenerating liver against ‘HCC’ CD133+ cells isolated from proto-oncogene driven and inflammation-associated HCC revealed preferential overexpression of SERPINA12 in HCC but not fetal and regenerating liver cells. SERPINA12 upregulation in HCC is tightly associated with aggressive clinical and stemness features, including survival, tumor stage, cirrhosis, and stemness signatures related to embryonic stem cells, oncogenic dedifferentiation and undifferentiated HCC status. Enrichment of SERPINA12 in HCC is mediated by promoter binding of the well-recognized β-catenin effector TCF7L2 to drive SERPINA12 transcriptional activity. Functional characterization identified a unique and novel role of endogenous SERPINA12 in promoting self-renewal, therapy resistance and metastatic abilities. Mechanistically, SERPINA12 functioned through binding to GRP78, resulting in a hyperactivated AKT/GSK3β/β-catenin signaling cascade, forming a positive feed-forward loop. Intravenous administration of rAVV8-shSERPINA12 sensitized HCC cells to sorafenib and impeded the CSC subset in an immunocompetent HCC mouse model. Collectively, our findings revealed that SERPINA12 is preferentially overexpressed in epithelial HCC CD133+ cells and is a key contributor to HCC initiation and progression by driving an AKT/β-catenin feed-forward loop. Citation Format: Huajian Yu, Lei Zhou, Jane Ho-Chun Loong, Ka-Hei Lam, Tin-Lok Wong, Kai-Yu Ng, Man Tong, Victor WS Ma, Yanyan Wang, Xiang Zhang, Terence K Lee, Jing-Ping Yun, Jun Yu, Stephanie Ma. SERPINA12 promotes the tumorigenic capacity of hepatocellular carcinoma stem cells through hyperactivation of AKT/β-catenin signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2433.
Abstract 3725: ABI1 regulates STAT3 transcription through a DNA binding activity
Authors: Xiang Li, Neeru Arya, Baylee A. Porter, Allysa P. Kemraj, Xuesen Dong, Dominique Frueh, Alaji Bah, Leszek Kotula
Journal: Cancer Research (2023)

Abstract Prostate cancer (PCa) is characterized by the complexity of oncogenic signaling and heterogeneity of transcriptional landscapes. Adaptor protein ABI1 is a tumor suppressor in PCa, as evidenced by its loss or downregulation in high-grade and metastatic tumors. STAT3 activation is a hallmark of high-risk prostate tumors. ABI1 loss is associated with STAT3 activation leading to transcriptional reprogramming and epithelial-mesenchymal-transition (EMT) of prostate cancer cells (Nath, Li et al. Cell Commun Signal. 2019). EMT changes involve several homeobox transcription factors. The fact that ABI1 contains a homeobox homology region (HHR) suggests the possibility that it plays a role in EMT by directly regulating transcriptional activity by DNA binding. To examine this hypothesis, we set out to analyze ABI1-DNA binding. Structural NMR studies and in-vitro protein-DNA binding assays confirmed ABI1 binding to DNA regulated by alternative spliced ABI1 Exon 4 region located on the C-terminus of ABI1 HHR. RNA-sequencing data and PCa cell lines qPCR assays reveal the alternative ABI1 Exon 4 spliced-in is enriched in high Gleason-scored PCa samples. ABI1 and STAT3 co-regulate their nuclear vs. cytoplasm localization, and the subsequent functional studies using PCa lines expressing wild type or HHR Exon 4 deletion mutant of ABI1 demonstrated that HHR regulates the STAT3 DNA binding patterns, STAT3 mediated chromatin structure programming as well as its transcription activities. We propose that ABI1 is a critical regulator of STAT3 activity during prostate cancer progression. Citation Format: Xiang Li, Neeru Arya, Baylee A. Porter, Allysa P. Kemraj, Xuesen Dong, Dominique Frueh, Alaji Bah, Leszek Kotula. ABI1 regulates STAT3 transcription through a DNA binding activity. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3725.
Abstract 3484: Oncohistone H2B-E76K alters gene expression &amp; cellular phenotype in a bronchial epithelial cell line
Authors: Kimberly Espinoza Pereira, Richard L. Bennett, Jixiu Shan, Jay Sarthy, Jonathan D. Licht
Journal: Cancer Research (2023)

Abstract The nucleosome is the basic unit of chromatin, comprising 147 bp of DNA wrapped around an octamer of core histone proteins H2A, H2B, H3 and H4. Compact chromatin acts as a barrier to gene expression and is a key property governing DNA replication and gene expression. Analyzing over 46,000 in cancer patient samples in cBioPortal, we characterized mutations located in canonical histone genes and found several recurrent missense mutations. Foremost among the identified mutations was a glutamate to lysine missense mutation at amino acid 76 of histone H2B (H2B-E76K) that disrupts histone H2B-H4 interaction. Previously, we demonstrated that exogenous expression of H2B-E76K disrupted nucleosome stability, altered chromatin accessibility, and gene expression. We developed a new model utilizing CRISPR “knock-in” technology to integrate the E76K mutation into the endogenous H2BC4 gene of the lung epithelial cell line BEAS-2B to create a homozygous and heterozygous H2B-E76K cell line. Although the mutant histone only accounts for about 2-5% of total histone H2B, expression of H2B-E76K catalyzed distinct changes in cell migration, proliferation, colony formation and gene expression. CUT&amp;RUN technology revealed mutant histones broadly incorporate throughout the genome. Gene set enrichment analysis (GSEA) revealed that H2B-E76K homozygous cells displayed expression changes similar to polycomb repressive complex 1 (PRC1) disruption or oncogenic KRAS expression. Using available datasets, we discovered that expression of H2B-E76K caused increased expression of PTN, PKIB, and CDH2, genes important in migration, epithelial-mesenchymal transition (EMT), and adhesion pathways. Furthermore, analysis of chromatin accessibility changes indicated that increased accessibility was significant in and around genes governing cell migration. Notably, H2B-E76K significantly increased heterogeneity of gene expression as measured using scRNA-seq. Together these results indicate that mutations disrupting histone structure may create millions of dysfunctional nucleosomes and new sites of “open” chromatin, resulting in loss of nucleosome-mediated gene repression and/or altered interactions with regulators of chromatin, fundamentally changing cell growth and migration properties to favor tumorigenesis. Citation Format: Kimberly Espinoza Pereira, Richard L. Bennett, Jixiu Shan, Jay Sarthy, Jonathan D. Licht. Oncohistone H2B-E76K alters gene expression &amp; cellular phenotype in a bronchial epithelial cell line [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3484.
Abstract 2681: Combination therapy of heme inhibitory protein (HeSP2) and Cyclopamine tartrate (CycT) with chemotherapeutic drugs is an effective strategy for treatment of TNBC
Authors: Parinaz Sadat Alemi, Maria del Carmen Chacon Castro, Eranda Berisha, Zakia Akter, Li Zhang
Journal: Cancer Research (2023)

Abstract Breast cancer (BC) is the second leading cause of cancer death in women. Among the four main types of BC, triple-negative breast cancer (TNBC) accounts for 10 to 15% of BC. Although most TNBC patients have a poor prognosis, there are subsets of patients with tumors that respond well to chemotherapy. However, the outcome of chemotherapy in TNBC worsens over time due to the high expression of the oxidative phosphorylation (OXPHOS) complex. Likewise, drug resistant TNBC cells depend on OXPHOS; targeting oxidative metabolism and mitochondrial respiration can potentially overcome their drug resistance. Our lab recently engineered a heme-sequestering protein 2 (HeSP2) based on HasA hemophore. HeSP2 can effectively inhibit heme uptake and decrease the OXPHOS levels in cancer cells due to its high affinity for heme. Another agent, cyclopamine tartrate (CycT), previously known as a modulator of hedgehog signaling and mitochondrial respiration, can inhibit heme synthesis and reduce the OXPHOS levels. Therefore, using these heme-targeting agents in combination with chemotherapy could be an effective strategy to increase the therapeutic efficacy in TNBC. Cisplatin and etoposide are two chemotherapeutic drugs that have recently been used for treating TNBC. For this purpose, we examine the combination therapy of our OXPHOS inhibitory agents, HeSP2 and CycT, with cisplatin and etoposide in TNBC. In vitro experiment using three different TNBC cell lines, 4T1-Fluc-Neo, EMT6_Fluc_Puro, and MDA-MBA-231 confirmed the inhibitory effect of both HeSP2 and CycT in cell proliferation and colony formation in combination with or without chemo drugs. Results indicate that combination therapy significantly reduced the proliferation and inhibited colony formation in TNBC cells. As HeSP2 and CycT are therapeutic agents that reduce hypoxia and OXPHOS, they may also delay the emergence of drug resistance in cancer cells treated with chemotherapy. Our results indicate that HeSP2 and CycT in combination with chemotherapy drugs could serve as a promising therapy to diminish the tumorigenic function in TNBC and overcome resistance to chemotherapy. Citation Format: Parinaz Sadat Alemi, Maria del Carmen Chacon Castro, Eranda Berisha, Zakia Akter, Li Zhang. Combination therapy of heme inhibitory protein (HeSP2) and Cyclopamine tartrate (CycT) with chemotherapeutic drugs is an effective strategy for treatment of TNBC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2681.